This invention relates to the field of pharmaceutical chemistry, and provides an advantageous process for preparing group of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[B]thiophen es. In particular, the invention relates to an improved process for preparing intermediates, i.e., dialkoxy benzo[B]thiophenes, useful for preparing such thiophenes. The process provides the desired compounds in excellent yield on a large scale without mixing problems.
The preparation of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]benzo[B]thiophen es through a dialkoxy benzo[B]thiophene intermediate was described in U.S. Pat. No. 4,380,635. The process described in that patent relies on the intramolecular cyclization of .alpha.-(3-methoxyphenyl-thio)-4-methoxyacetophenone in polyphosphoric acid (PPA). Heating the acetophenone starting material in PPA at about 85.degree. C. for about 1 hour provides an approximately 3:1 mixture of two isomers, 6-methoxy-2-(4-methoxyphenyl)benzo[B]thiophene and 4-methoxy-2-(4-methoxyphenyl)benzo[B]thiophene. When this transformation is conducted on a manufacturing scale, the isomeric benzo[B]thiophenes precipitate and produce a thick paste that cannot be stirred adequately in conventional manufacturing equipment.
Use of a solvent to alleviate the problem caused by a paste in a different reaction scheme has been attempted by Guy et al., Synthesis, 222 (1980). However, when this approach is applied to the instant scheme, the addition of a solvent results in incomplete cyclization of the starting acetophenone, incomplete rearrangement of 6-methoxy-3-(4-methoxyphenyl)benzo[B]thiophene, and dramatically increased reaction times. Thus, there is a need for a method to convert .alpha.-(-methoxyphenylthio)-4-methoxyacetophenone into 6-methoxy-3-(4-methoxyphenyl)benzo[B]thiophene in suitable yield in acceptable reaction times without generating a paste that prevents adequate mixing of the reaction mixture.
Most of the compounds prepared by the process of this invention are taught in U.S. Pat. No. 4,133,814, incorporated herein by reference.